Olaparib Proves Versatile When Paired With AKT Inhibitor

Timothy Yap, MD, PhD

The combination of the PARP inhibitor olaparib with the novel AKT-targeting agent AZD5363 generated responses in a variety of tumor types among patients with and without BRCA1/2 mutations, demonstrating that a simultaneous attack on the two pathways is a safe and potentially versatile strategy, according to research presented at the 2015 AACR Annual Meeting.

The phase I ComPAKT trial also was noteworthy because the study employed a novel design that enabled investigators to test the combination at different dosing levels and schedules with 20 patients in less than 8 months, researchers said.

The two-drug regimen elicited confirmed partial responses in four patients, according to Timothy Yap, MD, PhD, a clinician-scientist and consultant medical oncologist at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London who helped lead the trial.

The responders included one patient with BRCA1/2 wild-type ovarian cancer, two patients with BRCA1/2-mutant breast cancer, and one person with BRCA1-mutant ovarian cancer, Yap said in a statement.

In addition, two patients have experienced ongoing, prolonged disease stabilization, including one person with breast cancer of unknown BRCA status and another with peritoneal mesothelioma. Another patient with BRCA1/2-mutant advanced prostate cancer achieved a radiologic response measured by MRI and prostate-specific antigen levels that is ongoing after 11 months, Yap said.

“These early results are very exciting because preclinical data had suggested that the olaparib and AZD5363 combination had the potential to be effective in a much wider population of patients than just those harboring germline BRCA1/2 mutations,” said Yap.

Olaparib became the first PARP inhibitor to gain FDA approval in December 2014. The drug is indicated as monotherapy for patients with germline BRCA-mutated advanced ovarian cancer who have received ≥3 prior lines of chemotherapy.

Resistance develops in the majority of patients who receive PARP inhibitors, and researchers were seeking to increase activity by adding an agent that targets the AKT pathway, lead study author Vasiliki Michalarea, MD, said in presenting the findings during a plenary session at the conference.

The trial evaluated the combination regimen in patients with 10 different tumor types: six ovarian, three breast, two colorectal, two mesothelioma, two prostate, and one each of bladder, cervical, gastrointestinal stromal tumor, pancreatic, and uterine.

Participants were divided between two dosing schedules, with three different dose levels in each schedule. All patients received 300-mg tablets of olaparib twice daily, along with escalating doses of AZD5363.

Yap said the trial appears to be the first to use an intrapatient dose-escalation design to test targeted therapies. “This design allowed us to safely complete the dose-escalation phase with at least six evaluable patients at each dose level, and in two schedules of the combination with just 20 patients in 7.5 months, which is unprecedented,” said Yap.

As a result of this approach, researchers were able to determine that 300 mg of olaparib twice daily along with 640 mg of AZD5363 twice daily for two days each week is the appropriate dosage to move forward into phase II testing.

Michalarea said toxicities were similar between the dose levels and schedules, with grade 1/2 nausea, fatigue, diarrhea, and vomiting reported most frequently. Grade 3 toxicities included hyperglycemia, transaminitis, and fatigue.

Michalarea said the next step in the research involves an expansion phase at the established dosing level and schedule with two cohorts: (1) patients with germline BRCA1/2-mutated cancers including individuals who have received prior PARP inhibitors and have platinum-resistant tumors; and (2) patients with advanced cancers with clinical features of BRCAness or relevant somatic mutations.

Michalarea V, Lorente D, Lopez J, et al. Accelerated phase I trial of 2 schedules of the combination of the PARP inhibitor Olaparib (Ola) and AKT inhibitor AZD5363 (AZD) using a novel intrapatient (intrapt) dose escalation design in advanced cancer pts. Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 8529.

<<<

View more from the 2015 AACR Annual Meeting